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The HCN channel voltage sensor undergoes a large downward motion during hyperpolarization


Voltage-gated ion channels (VGICs) contain positively charged residues within the S4 helix of the voltage-sensing domain (VSD) that are displaced in response to changes in transmembrane voltage, promoting conformational changes that open the pore. Pacemaker hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are unique among VGICs because their open probability is increased by membrane hyperpolarization rather than depolarization. Here we measured the precise movement of the S4 helix of a sea urchin HCN channel using transition metal ion fluorescence resonance energy transfer (tmFRET). We show that the S4 undergoes a substantial (~10 Å) downward movement in response to membrane hyperpolarization. Furthermore, by applying distance constraints determined from tmFRET experiments to Rosetta modeling, we reveal that the carboxy-terminal part of the S4 helix exhibits an unexpected tilting motion during hyperpolarization activation. These data provide a long-sought glimpse of the hyperpolarized state of a functioning VSD and also a framework for understanding the dynamics of reverse gating in HCN channels.

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Fig. 1: PCF simultaneously measures current and Anap fluorescence in HCN channels.
Fig. 2: Hyperpolarization-dependent change in Anap fluorescence of spHCN channels with l-Anap incorporated into the S4 voltage sensor.
Fig. 3: tmFRET detects a hyperpolarization-dependent downward movement of S4 in spHCN-S346Anap channels.
Fig. 4: The distance change measured by ACCuRET decreases as Anap is positioned closer to the C-terminal end of S4.
Fig. 5: Rosetta model of S4 movement in HCN channels based on experimentally determined distance constraints.

Data availability

The coordinate files of the State 1 and State 2 models were deposited in PDB-dev ( with accession code PDBDEV_00000032. Source data for Figs. 3 and 4 and Supplementary Fig. 6 are available online. Other data are available from the corresponding author upon reasonable request.

Code availability

Rosetta scripts used for the modeling are in Supplementary Dataset 1.


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We thank X. Optiz-Araya and S. Haraguchi for animal care and surgical support; S.E. Gordon, L. Delemotte and all members of the Zagotta laboratory for their helpful advice and support; D. Farrell for help with the PDB-dev submission; and L. Anson for comments on the manuscript. This work was funded by NIH Grants (nos. R01EY010329, R01MH102378 and R01GM125351 to W.N.Z. and no. F32NS077622 to T.K.A.) and an American Heart Association Award (no. 14CSA20380095 to W.N.Z.).

Author information

Authors and Affiliations



G.D., T.K.A. and W.N.Z. conceived and designed experiments and G.D. performed experiments. T.K.A. performed pilot experiments. F.D. designed and performed Rosetta-based computational modeling. G.D., T.K.A., F.D. and W.N.Z. analyzed data. W.N.Z. and G.D. wrote the manuscript. G.D., T.K.A., F.D. and W.N.Z. edited the manuscript.

Corresponding author

Correspondence to William N. Zagotta.

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The authors declare no competing interests.

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Peer review information: Inês Chen was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

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Integrated supplementary information

Supplementary Figure 1 Electrophysiological properties of spHCN channels with incorporated Anap.

a, Left: representative current traces of wild-type spHCN channels in the absence or the presence of 1 mM cAMP. In the absence of cyclic nucleotide, the spHCN channel rapidly inactivates with hyperpolarization. Right: representative current traces from wild-type spHCN channels elicited by a series of hyperpolarizing voltage pulses from 0 mV to -110 mV with 10 mV steps, in the presence of 1 mM cAMP. b, Representative current traces from spHCN channels with L-Anap incorporated at different sites elicited by a series of hyperpolarizing voltage pulses from 0 mV to -120 mV, in the presence of 1 mM cAMP.

Supplementary Figure 2 Correlation of the Anap fluorescence and the YFP fluorescence and estimation of the quantum yields of L-Anap.

a-e, Plots of Anap versus YFP fluorescence intensities from multiple patches for the various L-Anap sites in spHCN. The slopes of the linear fit were used to calculate the L-Anap brightness relative to YFP. f, From the brightness of L-Anap at 0 mV and -100 mV, the quantum yields were estimated assuming the extinction coefficient of L-Anap was unchanged at different sites and different voltages.

Supplementary Figure 3 Emission spectra for L-Anap at each position in spHCN.

a-e, Emission spectra of L-Anap measured with a spectrograph for the indicated positions in spHCN at 0 mV and -100 mV. These spectra were fit with emission spectra for free L-Anap in solution, measured with a fluorometer shifted so that the peak positions are the same (black traces). The small peak at about 530 nm most likely corresponds to direct excitation of YFP. Also shown is the absorption spectra of Cu2+-TETAC (blue). f, Summary of the peak wavelength of the Anap emission for the various Anap sites in spHCN (n = 3 - 4, *p < 0.05). Error bars are s.e.m.

Supplementary Figure 4 ACCuRET between an Anap site in the S1 helix and the transition metal ion site in the HCN domain.

a, Cartoon showing the W218 Anap site and L186C modified by Cu2+-TETAC. b, Simultaneous current and Anap fluorescence recordings of spHCN-W218Anap channels. The Anap fluorescence did not change appreciably with -100 mV voltage pulses in the presence of 1 mM cAMP. c, Summary of the fractional Cu2+-TETAC quenching of Anap fluorescence at the W218 site, without and with the introduced cysteine L186C, at 0 mV and -100 mV (n = 4, error bars are s.e.m.). d, FRET efficiency calculated using the quenching data in panel c and Equation 1 (see Methods). e, Summary showing the distances of the W218/L186 FRET pair at 0 mV and -100 mV, calculated from the FRET efficiency in panel d and the FCG equation.

Supplementary Figure 5 Cu2+-TETAC binding to L186C site does not significantly change the electrophysiological properties of spHCN channels.

a-d, Left: representative current traces of spHCN-L186C channels with L-Anap incorporated at S346, L348, S353, and W355 sites of the S4 helix before and after applying 10 µM Cu2+-TETAC. Currents were recorded in the inside-out patch configuration and elicited by a series of hyperpolarizing voltage pulses from 0 mV to -110 mV (-100 mV for S353) with 10 mV steps, in the presence of 1 mM cAMP. Right: Normalized G-V relationships for the same recordings on the left before and after applying 10 µM Cu2+-TETAC. e, Time course of the Anap fluorescence for spHCN-W355Anap, L186C channels before and during application of 10 µM Cu2+-TETAC, illustrating that Anap fluorescence was not further decreased after 2 mins of applying Cu2+-TETAC compared to 1 min. This suggests the labeling of L186C was complete within 1 minute of Cu2+-TETAC application. n = 3, error bars are s.e.m.

Supplementary Figure 6 Different methods for correcting background quenching produce similar measurements of FRET efficiency.

a and b, FRET efficiency of the various FRET pairs on spHCN channels based on the fractional quenching data in Fig 4c, calculated by the equations E1 and E2 (see Methods), respectively.

Source data

Supplementary Figure 7 Alternative Rosetta models at -100 mV using different weights for experimentally-determined distance constraints.

Structure of 11 models varying the weights of experimentally-determined distance constraints from 50% to 200% of that used for the model in Fig. 5 (weight of 15, also see Methods). The green-colored S4 helix is the model shown in Fig. 5. The S4 helices in the other 10 models are shown in different colors.

Supplementary Figure 8 Fluorescence properties of L-Anap.

a, Emission spectra of free L-Anap in different solvents. Insert: overlap of spectra in the different solvents illustrates that the shape of the spectra is not appreciably affected by these different solvents. b, Emission spectra of L-Anap using the spectrograph attached to the patch-clamp microscope, using different slit widths. Slit 1 width: 5.9 µm; slit 2 width: 10.7 µm; slit 3 width: 24.8 µm. The shape of the spectra is not appreciably affected by different slit widths up to 25 µm, much larger than the diameter of our patches. c, Absorption spectra of free L-Anap in different solvents. The spectra were normalized to the extinction coefficient (17,500 M-1 cm-1) of L-Anap in EtOH at 360 nm as previously reported by Chatterjee et al. 2013. In our estimates of the quantum yield of Anap incorporated into the channel, we assume the environmental change in fluorescence intensity was entirely due to a change in quantum yield and not extinction coefficient.

Supplementary information

Supplementary Information

Supplementary Figures 1–8, Supplementary Table 1

Reporting Summary

Supplementary Dataset 1

Rosetta.sym file, Rosetta.xml file, file, Rosetta State 1 cen.cst file, Rosetta State 1 fa.cst file, Rosetta State 2 cen.cst file, Rosetta State 2 fa.cst file.

Supplementary Video 1

Patch-clamp fluorometry image of spHCN-S346Anap channels in response to a repetitive –100 mV hyperpolarizing voltage in the presence of 1 mM cAMP in the bath. The upper left bar indicates three one-second pulses to –100 mV interspersed with one-second intervals at 0 mV. The holding potential is 0 mV. Scale bar on the lower left is 15 μm.

Supplementary Video 2

Patch-clamp fluorometry image of spHCN-W355Anap channels in response to a –100 mV hyperpolarizing voltage in the presence of 1 mM cAMP in the bath. The upper left bar indicates a two-second pulse to –100 mV (the same duration as in Fig. 2b,d). Scale bar on the lower left is 15 μm.

Supplementary Video 3

A morph between the 0 mV (State 1) and –100 mV (State 2) state Rosetta models. The morph highlights the red/blue charge-smoothed surface of the HCN domain and the S1–S3 helices which the charged arginines and lysines of the S4 helix are interacting with. This qualitative vacuum electrostatic surface is automatically generated using the PyMOL software ( with red color representing the negatively charged surface and blue color representing positively charged surface.

Supplementary Video 4

Rosetta model of the hyperpolarization-induced S4 voltage sensor movement in the spHCN channel. The movie shows a morph between the Rosetta model at 0 mV (State 1) and the Rosetta model at –100 mV (State 2), highlighting the distance changes for the specific Anap sites between these two states.

Supplementary Video 5

Comparison of three different examples of S4 movement in VGIC family. Model of S4 movement in spHCN channels (left), S4 movement in TPCs (middle) and S4 movement in VSD2 of Nav channels (right). The model in the middle is a morph between the ‘up’ state of VSD2 S4 in mouse TPC1 (PDB: 6C96) and the ‘down’ state of the VSD2 S4 in Arabidopsis TPC1 (PDB: 5E1J). The model on the right is a morph between the ‘up’ state of S4 in Nav1.7-VSD2 (PDB: 6N4Q) and the ‘down’ state of S4 in Nav1.7- VSD2 (PDB: 6N4R) in complex with the gating modifier toxin ProTx2 (not shown).

Source Data for Fig. 3

Source Data for Fig. 4

Source Data for Supplementary Fig. 6

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Dai, G., Aman, T.K., DiMaio, F. et al. The HCN channel voltage sensor undergoes a large downward motion during hyperpolarization. Nat Struct Mol Biol 26, 686–694 (2019).

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